Browsing by Author "Gasier, Heath G"
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Item Open Access 5-Hydroxymethylfurfural reduces skeletal muscle superoxide production and modifies force production in rats exposed to hypobaric hypoxia.(Physiological reports, 2023-07) Ciarlone, Geoffrey E; Swift, Joshua M; Williams, Brian T; Mahon, Richard T; Roney, Nicholas G; Yu, Tianzheng; Gasier, Heath GDecreased blood-tissue oxygenation at high altitude (HA) increases mitochondrial oxidant production and reduces exercise capacity. 5-Hydroxymethylfurfural (5-HMF) is an antioxidant that increases hemoglobin's binding affinity for oxygen. For these reasons, we hypothesized that 5-HMF would improve muscle performance in rats exposed to a simulated HA of ~5500 m. A secondary objective was to measure mitochondrial activity and dynamic regulation of fission and fusion because they are linked processes impacted by HA. Fisher 344 rats received 5-HMF (40 mg/kg/day) or vehicle during exposure to sea level or HA for 72 h. Right ankle plantarflexor muscle function was measured pre- and post-exposure. Post-exposure measurements included arterial blood gas and complete blood count, flexor digitorum brevis myofiber superoxide production and mitochondrial membrane potential (ΔΨm), and mitochondrial dynamic regulation in the soleus muscle. HA reduced blood oxygenation, increased superoxide levels and lowered ΔΨm, responses that were accompanied by decreased peak isometric torque and force production at frequencies >75 Hz. 5-HMF increased isometric force production and lowered oxidant production at sea level. In HA exposed animals, 5-HMF prevented a decline in isometric force production at 75-125 Hz, prevented an increase in superoxide levels, further decreased ΔΨm, and increased mitochondrial fusion 2 protein expression. These results suggest that 5-HMF may prevent a decrease in hypoxic force production during submaximal isometric contractions by an antioxidant mechanism.Item Open Access Acclimation of C2C12 myoblasts to physiological glucose concentrations for in vitro diabetes research(Life Sciences, 2018-10) Dohl, Jacob; Foldi, Jonathan; Heller, Julian; Gasier, Heath G; Deuster, Patricia A; Yu, TianzhengItem Open Access Acute resistance exercise augments integrative myofibrillar protein synthesis(Metabolism, 2012-02) Gasier, Heath G; Fluckey, James D; Previs, Stephen F; Wiggs, Michael P; Riechman, Steven EItem Open Access Adrenoceptor blockade modifies regional cerebral blood flow responses to hyperbaric hyperoxia: Protection against CNS oxygen toxicity.(Journal of applied physiology (Bethesda, Md. : 1985), 2018-07-19) Gasier, Heath G; Demchenko, Ivan T; Zhilyaev, Sergei Yu; Moskvin, Alexander N; Krivchenko, Alexander I; Piantadosi, Claude AExposure to extreme-hyperbaric oxygen (HBO2), > 5-6 atmospheres absolute (ATA), produces baroreflex impairment, sympathetic hyperactivation, hypertension, tachycardia, and cerebral hyperemia, known as Phase II, culminating in seizures. We hypothesized that attenuation of the effects of high sympathetic outflow would preserve regional cerebral blood flow (rCBF) and protect against HBO2-induced seizures. To explore this possibility, we tested four adrenoceptor antagonists in conscious and anesthetized rats exposed to HBO2 at 5 and 6 ATA, respectively: phentolamine (nonselective α1 and 2), prazosin (selective α1), propranolol (nonselective β1 and 2) and atenolol (selective β1). In conscious rats, 4 drug-doses were administered to rats prior to HBO2 exposures, and seizure latencies were recorded. Drug-doses that provided similar protection against seizures were administered before HBO2 exposures in anesthetized rats to determine the effects of adrenoceptor blockade on mean arterial pressure, heart rate, rCBF and EEG spikes. All four drugs modified cardiovascular and rCBF responses in HBO2 that aligned with epileptiform discharges, but only phentolamine and propranolol effectively increased EEG spike latencies by ~20 and 36 min, respectively. When phentolamine and propranolol were delivered during HBO2 at the onset of phase II, only propranolol led to sustained reductions in heart rate and rCBF, preventing the appearance of epileptiform discharges. The enhanced effectiveness of propranolol may extend beyond β-adrenoceptor blockade, i.e. membrane stability and reduced metabolic activity. These results indicate that adrenoceptor drug pre-treatment will minimize the effects of excessive sympathetic outflow on rCBF and extend HBO2 exposure time.Item Open Access Astaxanthin but not quercetin preserves mitochondrial integrity and function, ameliorates oxidative stress, and reduces heat‐induced skeletal muscle injury(Journal of Cellular Physiology, 2019-08) Yu, Tianzheng; Dohl, Jacob; Chen, Yifan; Gasier, Heath G; Deuster, Patricia AItem Open Access Baroreceptor afferents modulate brain excitation and influence susceptibility to toxic effects of hyperbaric oxygen.(Journal of applied physiology (Bethesda, Md. : 1985), 2014-09) Demchenko, Ivan T; Gasier, Heath G; Zhilyaev, Sergei Yu; Moskvin, Alexander N; Krivchenko, Alexander I; Piantadosi, Claude A; Allen, Barry WUnexplained adjustments in baroreflex sensitivity occur in conjunction with exposures to potentially toxic levels of hyperbaric oxygen. To investigate this, we monitored central nervous system, autonomic and cardiovascular responses in conscious and anesthetized rats exposed to hyperbaric oxygen at 5 and 6 atmospheres absolute, respectively. We observed two contrasting phases associated with time-dependent alterations in the functional state of the arterial baroreflex. The first phase, which conferred protection against potentially neurotoxic doses of oxygen, was concurrent with an increase in baroreflex sensitivity and included decreases in cerebral blood flow, heart rate, cardiac output, and sympathetic drive. The second phase was characterized by baroreflex impairment, cerebral hyperemia, spiking on the electroencephalogram, increased sympathetic drive, parasympatholysis, and pulmonary injury. Complete arterial baroreceptor deafferentation abolished the initial protective response, whereas electrical stimulation of intact arterial baroreceptor afferents prolonged it. We concluded that increased afferent traffic attributable to arterial baroreflex activation delays the development of excessive central excitation and seizures. Baroreflex inactivation or impairment removes this protection, and seizures may follow. Finally, electrical stimulation of intact baroreceptor afferents extends the normal delay in seizure development. These findings reveal that the autonomic nervous system is a powerful determinant of susceptibility to sympathetic hyperactivation and seizures in hyperbaric oxygen and the ensuing neurogenic pulmonary injury.Item Open Access Calcium and vitamin D supplementation and bone health in Marine recruits: Effect of season(Bone, 2019-06) Gaffney-Stomberg, Erin; Nakayama, Anna T; Guerriere, Katelyn I; Lutz, Laura J; Walker, Leila A; Staab, Jeffery S; Scott, Jonathan M; Gasier, Heath G; McClung, James PItem Open Access Carbon Monoxide and Exercise Prevents Diet-Induced Obesity and Metabolic Dysregulation Without Affecting Bone.(Obesity (Silver Spring, Md.), 2020-05) Gasier, Heath G; Yu, Tianzheng; Swift, Joshua M; Metzger, Corrine E; McNerny, Erin M; Swallow, Elizabeth A; Piantadosi, Claude A; Allen, Matthew RObjective
Carbon monoxide (CO) may counteract obesity and metabolic dysfunction in rodents consuming high-fat diets, but the skeletal effects are not understood. This study investigated whether low-dose inhaled CO (250 ppm) with or without moderate intensity aerobic exercise (3 h/wk) would limit diet-induced obesity and metabolic dysregulation and preserve bone health.Methods
Obesity-resistant (OR) rats served as controls, and obesity-prone (OP) rats were randomized to sedentary, sedentary plus CO, exercise, or CO plus exercise. For 10 weeks, OP rats consumed a high-fat, high-sucrose diet, whereas OR rats consumed a low-fat control diet. Measurements included indicators of obesity and metabolism, bone turnover markers, femoral geometry and microarchitecture, bone mechanical properties, and tibial morphometry.Results
A high-fat, high-sucrose diet led to obesity, hyperinsulinemia, and hyperleptinemia, without impacting bone. CO alone led only to a modest reduction in weight gain. Exercise attenuated weight gain and improved the metabolic profile; however, bone fragility increased. Combined CO and exercise led to body mass reduction and a metabolic state similar to control OR rats and prevented the exercise-induced increase in bone fragility.Conclusions
CO and aerobic exercise training prevent obesity and metabolic sequelae of nutrient excess while stabilizing bone physiology.Item Open Access Cardiometabolic Health in Submariners Returning from a 3-Month Patrol(Nutrients) Gasier, Heath G; Young, Colin R; Gaffney-Stomberg, Erin; McAdams, Douglas C; Lutz, Laura J; McClung, James PItem Open Access Comparison of Body Composition Assessed by Dual-Energy X-Ray Absorptiometry and BMI in Current and Former U.S. Navy Service Members.(PloS one, 2015-01) Gasier, Heath G; Hughes, Linda M; Young, Colin R; Richardson, Annely MBackground
Little is known of the diagnostic accuracy of BMI in classifying obesity in active duty military personnel and those that previously served. Thus, the primary objectives were to determine the relationship between lean and fat mass, and body fat percentage (BF%) with BMI, and assess the agreement between BMI and BF% in defining obesity.Methods
Body composition was measured by dual-energy X-ray absorptiometry in 462 males (20-91 years old) who currently or previously served in the U.S. Navy. A BMI of ≥ 30 kg/m2 and a BF% ≥ 25% were used for obesity classification.Results
The mean BMI (± SD) and BF% were 28.8 ± 4.1 and 28.9 ± 6.6%, respectively, with BF% increasing with age. Lean mass, fat mass, and BF% were significantly correlated with BMI for all age groups. The exact agreement of obesity defined by BMI and BF% was fair (61%), however, 38% were misclassified by a BMI cut-off of 30 when obesity was defined by BF%.Conclusions
From this data we determined that there is a good correlation between body composition and BMI, and fair agreement between BMI and BF% in classifying obesity in a group of current and former U.S. Navy service members. However, as observed in the general population, a significant proportion of individuals with excess fat are misclassified by BMI cutoffs.Item Open Access Curcumin Ameliorates Heat-Induced Injury through NADPH Oxidase-Dependent Redox Signaling and Mitochondrial Preservation in C2C12 Myoblasts and Mouse Skeletal Muscle.(The Journal of nutrition, 2020-09) Yu, Tianzheng; Dohl, Jacob; Wang, Li; Chen, Yifan; Gasier, Heath G; Deuster, Patricia ABackground
Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and the mitochondrial electron transport chain are the primary sources of reactive oxygen species (ROS). Previous studies have shown that severe heat exposure damages mitochondria and causes excessive mitochondrial ROS production that contributes to the pathogenesis of heat-related illnesses.Objectives
We tested whether the antioxidant curcumin could protect against heat-induced mitochondrial dysfunction and skeletal muscle injury, and characterized the possible mechanism.Methods
Mouse C2C12 myoblasts and rat flexor digitorum brevis (FDB) myofibers were treated with 5 μM curcumin; adult male C57BL/6J mice received daily curcumin (15, 50, or 100 mg/kg body weight) by gavage for 10 consecutive days. We compared ROS levels and mitochondrial morphology and function between treatment and nontreatment groups under unheated or heat conditions, and investigated the upstream mechanism and the downstream effect of curcumin-regulated ROS production.Results
In C2C12 myoblasts, curcumin prevented heat-induced mitochondrial fragmentation, ROS overproduction, and apoptosis (all P < 0.05). Curcumin treatment for 2 and 4 h at 37°C induced increases in ROS levels by 42% and 59% (dihydroethidium-derived fluorescence), accompanied by increases in NADPH oxidase protein expression by 24% and 32%, respectively (all P < 0.01). In curcumin-treated cells, chemical inhibition and genetic knockdown of NADPH oxidase restored ROS to levels similar to those of controls, indicating NADPH oxidase mediates curcumin-stimulated ROS production. Moreover, curcumin induced ROS-dependent shifting of the mitochondrial fission-fusion balance toward fusion, and increases in mitochondrial mass by 143% and membrane potential by 30% (both P < 0.01). In rat FDB myofibers and mouse gastrocnemius muscles, curcumin preserved mitochondrial morphology and function during heat stress, and prevented heat-induced mitochondrial ROS overproduction and tissue injury (all P < 0.05).Conclusions
Curcumin regulates ROS hormesis favoring mitochondrial fusion/elongation, biogenesis, and improved function in rodent skeletal muscle. Curcumin may be an effective therapeutic target for heat-related illness and other mitochondrial diseases.Item Open Access Effects of oral sodium nitrate on forearm blood flow, oxygenation and exercise performance during acute exposure to hypobaric hypoxia (4300 m)(Nitric Oxide, 2017-09) Gasier, Heath G; Reinhold, Anthony R; Loiselle, Allison R; Soutiere, Shawn E; Fothergill, David MItem Open Access Effects of striatal nitric oxide production on regional cerebral blood flow and seizure development in rats exposed to extreme hyperoxia.(Journal of applied physiology (Bethesda, Md. : 1985), 2015-12) Gasier, Heath G; Demchenko, Ivan T; Allen, Barry W; Piantadosi, Claude AThe endogenous vasodilator and signaling molecule nitric oxide has been implicated in cerebral hyperemia, sympathoexcitation, and seizures induced by hyperbaric oxygen (HBO2) at or above 3 atmospheres absolute (ATA). It is unknown whether these events in the onset of central nervous system oxygen toxicity originate within specific brain structures and whether blood flow is diverted to the brain from peripheral organs with high basal flow, such as the kidney. To explore these questions, total and regional cerebral blood flow (CBF) were measured in brain structures of the central autonomic network in anesthetized rats in HBO2 at 6 ATA. Electroencephalogram (EEG) recordings, cardiovascular hemodynamics, and renal blood flow (RBF) were also monitored. As expected, mean arterial blood pressure and total and regional CBF increased preceding EEG spikes while RBF was unaltered. Of the brain structures examined, the earliest rise in CBF occurred in the striatum, suggesting increased neuronal activation. Continuous unilateral or bilateral striatal infusion of the nitric oxide synthase inhibitor N(ω)-nitro-L-arginine methyl ester attenuated CBF responses in that structure, but global EEG discharges persisted and did not differ from controls. Our novel findings indicate that: 1) cerebral hyperemia in extreme HBO2 in rats does not occur at the expense of renal perfusion, highlighting the remarkable autoregulatory capability of the kidney, and 2) in spite of a sentinel increase in striatal blood flow, additional brain structure(s) likely govern the pathogenesis of HBO2-induced seizures because EEG discharge latency was unchanged by local blockade of striatal nitric oxide production and concomitant hyperemia.Item Open Access Effects of vitamin D supplementation on salivary immune responses during Marine Corps basic training(Scandinavian Journal of Medicine & Science in Sports, 2019-09) Scott, Jonathan M; Kazman, Josh B; Palmer, Jeremy; McClung, James P; Gaffney-Stomberg, Erin; Gasier, Heath GItem Open Access GAT inhibition preserves cerebral blood flow and reduces oxidant damage to mitochondria in rodents exposed to extreme hyperbaric oxygen.(Frontiers in molecular neuroscience, 2022-01) Demchenko, Ivan T; Suliman, Hagir B; Zhilyaey, Sergey Y; Alekseeva, Olga S; Platonova, Tatyana F; Makowski, Matthew S; Piantadosi, Claude A; Gasier, Heath GOxygen breathing at elevated partial pressures (PO2's) at or more than 3 atmospheres absolute (ATA) causes a reduction in brain γ-aminobutyric acid (GABA) levels that impacts the development of central nervous system oxygen toxicity (CNS-OT). Drugs that increase brain GABA content delay the onset of CNS-OT, but it is unknown if oxidant damage is lessened because brain tissue PO2 remains elevated during hyperbaric oxygen (HBO2) exposures. Experiments were performed in rats and mice to measure brain GABA levels with or without GABA transporter inhibitors (GATs) and its influence on cerebral blood flow, oxidant damage, and aspects of mitochondrial quality control signaling (mitophagy and biogenesis). In rats pretreated with tiagabine (GAT1 inhibitor), the tachycardia, secondary rise in mean arterial blood pressure, and cerebral hyperemia were prevented during HBO2 at 5 and 6 ATA. Tiagabine and the nonselective GAT inhibitor nipecotic acid similarly extended HBO2 seizure latencies. In mice pretreated with tiagabine and exposed to HBO2 at 5 ATA, nuclear and mitochondrial DNA oxidation and astrocytosis was attenuated in the cerebellum and hippocampus. Less oxidant injury in these regions was accompanied by reduced conjugated microtubule-associated protein 1A/1B-light chain 3 (LC3-II), an index of mitophagy, and phosphorylated cAMP response element binding protein (pCREB), an initiator of mitochondrial biogenesis. We conclude that GABA prevents cerebral hyperemia and delays neuroexcitation under extreme HBO2, limiting oxidant damage in the cerebellum and hippocampus, and likely lowering mitophagy flux and initiation of pCREB-initiated mitochondrial biogenesis.Item Open Access Increased Antiseizure Effectiveness with Tiagabine Combined with Sodium Channel Antagonists in Mice Exposed to Hyperbaric Oxygen.(Neurotoxicity research, 2019-11) Demchenko, Ivan T; Zhilyaev, Sergei Yu; Alekseeva, Olga S; Krivchenko, Alexander I; Piantadosi, Claude A; Gasier, Heath GHyperbaric oxygen (HBO2) is acutely toxic to the central nervous system, culminating in EEG spikes and tonic-clonic convulsions. GABA enhancers and sodium channel antagonists improve seizure latencies in HBO2 when administered individually, while combining antiepileptic drugs from different functional classes can provide greater seizure latency. We examined the combined effectiveness of GABA enhancers (tiagabine and gabapentin) with sodium channel antagonists (carbamazepine and lamotrigine) in delaying HBO2-induced seizures. A series of experiments in C57BL/6 mice exposed to 100% oxygen at 5 atmospheres absolute (ATA) were performed. We predicted equally effective doses from individual drug-dose response curves, and the combinations of tiagabine + carbamazepine or lamotrigine were tested to determine the maximally effective combined doses to be used in subsequent experiments designed to identify the type of pharmacodynamic interaction for three fixed-ratio combinations (1:3, 1:1, and 3:1) using isobolographic analysis. For both combinations, the maximally effective combined doses increased seizure latency over controls > 5-fold and were determined to interact synergistically for fixed ratios 1:1 and 3:1, additive for 1:3. These results led us to explore whether the benefits of these drug combinations could be extended to the lungs, since a centrally mediated mechanism is believed to mediate hyperoxic-induced cardiogenic lung injury. Indeed, both combinations attenuated bronchoalveolar lavage protein content by ~ 50%. Combining tiagabine with carbamazepine or lamotrigine not only affords greater antiseizure protection in HBO2 but also allows for lower doses to be used, minimizing side effects, and attenuating acute lung injury.Item Open Access Insulin resistance syndrome blunts the mitochondrial anabolic response following resistance exercise(American Journal of Physiology-Endocrinology and Metabolism, 2010-09) Nilsson, Mats I; Greene, Nicholas P; Greene, Nicholas P; Dobson, Justin P; Wiggs, Michael P; Gasier, Heath G; Macias, Brandon R; Shimkus, Kevin L; Fluckey, James DMetabolic risk factors associated with insulin resistance syndrome may attenuate augmentations in skeletal muscle protein anabolism following contractile activity. The purpose of this study was to investigate whether or not the anabolic response, as defined by an increase in cumulative fractional protein synthesis rates (24-h FSR) following resistance exercise (RE), is blunted in skeletal muscle of a well-established rodent model of insulin resistance syndrome. Four-month-old lean ( Fa/?) and obese ( fa/fa) Zucker rats engaged in four lower body RE sessions over 8 days, with the last bout occurring 16 h prior to muscle harvest. A priming dose of deuterium oxide (2H2O) and 2H2O-enriched drinking water were administered 24 h prior to euthanization for assessment of cumulative FSR. Fractional synthesis rates of mixed (−5%), mitochondrial (−1%), and cytosolic (+15%), but not myofibrillar, proteins (−16%, P = 0.012) were normal or elevated in gastrocnemius muscle of unexercised obese rats. No statistical differences were found in the anabolic response of cytosolic and myofibrillar subfractions between phenotypes, but obese rats were not able to augment 24-h FSR of mitochondria to the same extent as lean rats following RE (+14% vs. +28%, respectively). We conclude that the mature obese Zucker rat exhibits a mild, myofibrillar-specific suppression in basal FSR and a blunted mitochondrial response to contractile activity in mixed gastrocnemius muscle. These findings underscore the importance of assessing synthesis rates of specific myocellular subfractions to fully elucidate perturbations in basal protein turnover rates and differential adaptations to exercise stimuli in metabolic disease.Item Open Access Iron deficiency and high-intensity running interval training do not impact femoral or tibial bone in young female rats(British Journal of Nutrition) Scott, Jonathan M; Swallow, Elizabeth A; Metzger, Corinne E; Kohler, Rachel; Wallace, Joseph M; Stacy, Alexander J; Allen, Matthew R; Gasier, Heath GAbstract In the USA, as many as 20 % of recruits sustain stress fractures during basic training. In addition, approximately one-third of female recruits develop Fe deficiency upon completion of training. Fe is a cofactor in bone collagen formation and vitamin D activation, thus we hypothesised Fe deficiency may be contributing to altered bone microarchitecture and mechanics during 12-weeks of increased mechanical loading. Three-week old female Sprague Dawley rats were assigned to one of four groups: Fe-adequate sedentary, Fe-deficient sedentary, Fe-adequate exercise and Fe-deficient exercise. Exercise consisted of high-intensity treadmill running (54 min 3×/week). After 12-weeks, serum bone turnover markers, femoral geometry and microarchitecture, mechanical properties and fracture toughness and tibiae mineral composition and morphometry were measured. Fe deficiency increased the bone resorption markers C-terminal telopeptide type I collagen and tartate-resistant acid phosphatase 5b (TRAcP 5b). In exercised rats, Fe deficiency further increased bone TRAcP 5b, while in Fe-adequate rats, exercise increased the bone formation marker procollagen type I N-terminal propeptide. In the femur, exercise increased cortical thickness and maximum load. In the tibia, Fe deficiency increased the rate of bone formation, mineral apposition and Zn content. These data show that the femur and tibia structure and mechanical properties are not negatively impacted by Fe deficiency despite a decrease in tibiae Fe content and increase in serum bone resorption markers during 12-weeks of high-intensity running in young growing female rats.Item Open Access Propranolol's Potential to Increase Survival Time in a Disabled Submarine(Aviation, Space, and Environmental Medicine, 2012-02-01) Reini, Seth A; Fothergill, David M; Gasier, Heath G; Horn, Wayne GItem Open Access Research report: Charcoal type used for hookah smoking influences CO production.(Undersea & hyperbaric medicine : journal of the Undersea and Hyperbaric Medical Society, Inc, 2015-07) Medford, Marlon A; Gasier, Heath G; Hexdall, Eric; Moffat, Andrew D; Freiberger, John J; Moon, Richard EA hookah smoker who was treated for severe carbon monoxide poisoning with hyperbaric oxygen reported using a different type of charcoal prior to hospital admission, i.e., quick-light charcoal. This finding led to a study aimed at determining whether CO production differs between charcoals commonly used for hookah smoking, natural and quick-light. Our hypothesis was that quick-light charcoal produces significantly more CO than natural charcoal. A medium-sized hookah, activated charcoal filter, calibrated syringe, CO gas analyzer and infrared thermometer were assembled in series. A single 9-10 g briquette of either natural or quick-light charcoal was placed atop the hookah bowl and ignited. CO output (ppm) and temperature (degrees C) were measured in three-minute intervals over 90 minutes. The mean CO levels produced by quick-light charcoal over 90 minutes was significantly higher (3728 ± 2028) compared to natural charcoal (1730 ± 501 ppm, p = 0.016). However, the temperature was significantly greater when burning natural charcoal (292 ± 87) compared to quick-light charcoal (247 ± 92 degrees C, p = 0.013). The high levels of CO produced when using quick-light charcoals may be contributing to the increase in reported hospital admissions for severe CO poisoning.